New Approaches to Catalyst Screening and Development

这项研究项目建立在内布拉斯加大学研究团队正在开发的平台上，该平台旨在利用酶作为催化记者，以促进反应发现和催化剂优化。这种方法被称为原位酶促筛选。该方法利用“报告酶”来提供一组感兴趣的平行有机/有机金属反应的相对速率的实时信息。平行筛选方法引起了学术界和工业界化学家的兴趣，因为它们能够识别用于靶向反应的新型催化剂的根本新转化。在制药业的过程化学组中，特别需要有重点的筛选，其中反应优化至关重要。该项目寻求开发新的酶筛选工具，该工具适用于各种温度，并利用目前尚不具备酶筛选功能的磷酸酯功能。该项目还将通过在化学/生物界面的跨学科研究环境中培训不同的本科生和研究生来帮助建设未来的STEM(科学、技术、工程和数学)劳动力队伍，包括有机、有机金属、分析和酶化学的元素。该项目将进一步探索和开发一种信息丰富的平行筛选方法，称为原位酶筛选(ISES)，它使用酶作为生物大分子传感器，直接向实验者提供读数。这项研究建立在该团队早期的概念验证研究的基础上，这些研究导致了与镍的催化不对称烯丙基胺化化学的第一个例子，镍是一种富含稀土的金属，并发现了一种有用的新转化，用于以多样性为导向的合成，称为硫氰化钯/碳环化。这项提案旨在全面推出“磷酸盐-ISES”和“热-ISES”筛选平台。前一个目标是因为具有二烷基磷酸功能的底物的出现和重要性，二烷基磷酸是过渡金属配位和特定化学的重要官能团。这些新的酶筛选平台是通过表达和测试筛选识别二烷基磷酸盐和/或在高温下工作的酶的候选酶来构建的。初步结果表明，在这种条件下，酶能产生UV/VIS信号，从而能够在高温下或在二烷基磷酸基官能团至关重要的反应中筛选候选的金属-配体组合。这些方法是在考虑到特定的靶向化学的情况下开发的，特别是催化不对称合成α-卤代乙烯基氨基酸作为潜在的PLP(吡哆醛磷酸)酶的基于机理的抑制剂。这一合成目标建立在该实验室的最新进展基础上，在该实验室中首次合成了四元，α-(1‘-氟)乙烯基氨基酸。这项工作的更广泛的科学影响包括为催化剂发现过程以及绿色和可持续化学开辟新的途径。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This research project builds on a platform being developed by the University of Nebraska research team to exploit enzymes as catalytic reporters to facilitate reaction discovery and catalyst optimization. This approach is termed In Situ Enzymatic Screening. The method utilizes ‘reporting enzymes’ to provide real-time information on the relative rates for a set of parallel organic/organometallic reactions of interest. Parallel screening methods are of interest to chemists in academia and industry as they enable the identification of fundamentally new transformations of novel catalysts for targeted reactions. There is a particular need for focused screening in process chemistry groups in the pharmaceutical industry, where reaction optimization is critical. This project seeks to develop new enzymatic screening tools that are applicable across a range of temperatures and that take advantage of phosphate ester functionality for which enzymatic screens are not yet available. The project will also help build the future STEM (science, technology, engineering, and mathematics) workforce by training a diverse group of undergraduate and graduate students in an interdisciplinary research environment at the chemistry/biology interface, including elements of organic, organometallic, analytical, and enzymatic chemistry. This project will further explore and develop an information-rich parallel screening method, termed In Situ Enzymatic Screening (ISES), that uses enzymes as biomacromolecular sensors to provide read-out directly to the experimentalist. This research builds upon the team's earlier proof-of-concept studies that led to the first examples of catalytic asymmetric allylic amination chemistry with nickel, an earth-abundant metal, and that uncovered a useful new transformation for diversity-oriented synthesis known as thiocyanopalladation/carbocyclization. This proposal seeks to fully launch the ‘phosphate-ISES’ and ‘thermal-ISES’ screening platforms. The former goal is motivated by the emergence and importance of substrates bearing dialkyl phosphate functionalities, an important functional group both for transition metal coordination and for specific chemistry. These new enzymatic screening platforms have been built by expressing and testing candidates for screening enzymes that recognize dialkyl phosphates and/or that operate at elevated temperatures. Preliminary results point to enzymes that produce a UV/vis signal under such conditions, enabling the screening of candidate metal-ligand combinations at elevated temperatures or in reactions where dialkyl phosphate functionalities are critical. These methods are being developed with specific targeted chemistry in mind, particularly the catalytic asymmetric synthesis of alpha-halovinyl amino acids as potential mechanism-based inhibitors for PLP (pyridoxal phosphate) enzymes. This synthetic goal builds on recent developments in this laboratory in which quaternary, alpha-(1’-fluoro) vinyl amino acids were synthesized for the first time. The scientific broader impacts of this work include opening new avenues for the catalyst discovery process and for green and sustainable chemistry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.